1. Field of the Invention
The present invention relates to diagnostic and therapeutic agents and compositions, methods of their use and processes for their preparation. More particularly, the invention relates to self-assembling heteropolymetailic chelates usefull for improving the contrast of x-ray, ultrasound, radionuclide and magnetic resonance (MR) images, and in therapeutic compositions.
2. Reported Developments
Metal chelates are useful for improving the contrast of X-ray, ultrasound, radionuclide and magnetic resonance (MR) images. Metal ions leading to an improvement of the contrast of medical images are usually too toxic to be injected as such and a wide variety of chelating ligands have been synthesized to ensure their complete elimination from the body. In all cases, the metal complexes must be thermodynamically stable and kinetically inert so as to limit dissociation in the body and the resulting toxicity as much as possible. New structures, either cyclic or linear, have been devised in recent years to achieve high stability and entirely new steric arrangements of heteroatoms such as N, O, P or S in aliphatic and/or aromatic frames have been suggested. Furthermore, reacting groups have been added to metal ligands so as to link them covalently or non-covalently to biological or synthetic macromolecules. A better tissue selectivity may then be achieved and special effects such as a higher relaxivity in MRI may be observed.
In MRI, highly stable chelates of paramagnetic ions are used to reduce the longitudinal and transverse relaxation times T.sub.1 and T.sub.2 of water (J. A. Peters et al., Prog. Nucl. Magn. Reson. Spectrosc. 1996, 28, 283). Various complexes of S state ions such as manganese(II), iron(IIl) and gadolinium(III) have received widespread attention. The Gd.sup.3+ ion is the preferred paramagnetic species because of its high magnetic moment and its slow electronic relaxation times but, as mentioned above, it must be embedded into a chelating agent before being injected intravenously in order to reduce its toxicity. Gadolinium complexes provide information regarding blood-brain barrier impairments and myocardial perfusion abnormalities. They also allow the assessment of the vascular system (carotid arteries, renal and iliac arteries) and the imaging of the liver (see for instance V. M. Runge, Diagn. Imag. Europ. 37-45, 1997). The Gd.sup.3+ ion has been successfully encapsulated by a variety of derivatives of DTPA (diethylenetriaminepentaacetic acid) or DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Moreover, the structure of these ligands has been chemically modified in order to increase the hydrophobicity of their Gd.sup.3+ complexes and thus favor an elimination through the liver and the bile rather than through the kidneys (J. F. Desreux et al., U.S. Pat. No. 5,358,704, 1993). The imaging of the liver is then greatly facilitated. Chemical alterations of the ligand structures have also been performed purposely to modify the physical parameters controlling relaxivity. The aim is to achieve a maximum relaxivity in the 5-60 MHz range which is the preferred frequency domain for imaging because of the better signal/noise ratio. For instance, covalent or non-covalent binding of a complex to a macromolecule leads to a reduction of its rotational correlation time and to a strong increase in relaxivity provided the macromolecule and the Gd.sup.3+ complex are rigidly linked together and rotate at about the same rate. In addition, the water exchange time between the inner coordination sphere of the metal ion and the bulk of the aqueous solution has been modified by altering structural features. Recently, amide groups in the DTPA unit have been shown to reduce the rate of exchange of water molecules(G. Gonzalez et al., J Phys. Chem. 98, 53-59, 1994). This reduction is detrimental to relaxivity when the chelate is associated to a macromolecule and should be avoided. Finally, it should be added that dysprosium(III) chelates have been found useful because of their very high magnetic moment (10.6 BM) that causes a loss of phase coherence and a pronounced reduction in signal intensity in T.sub.2 -weighted images.
Improving the contrast of X-ray images requires the use of chelates of metal ions that are able to absorb X-rays at least as well as iodine. These metallic ions should thus have atomic weights higher than 127 (for instance, the lanthanides, Ta, or Bi). Similar complexes can reflect or scatter ultrasound radiations sufficiently to alter the contrast of ultrasound images.
Radiopharmaceutical imaging makes use of short-lived radionuclides, such as .sup.68 Ga, .sup.90 Y, .sup.99m Tc, .sup.111 In, .sup.140 La, .sup.169 Yb, .sup.153 Sm and others. After complexation with a suitable ligand, these isotopes are often linked covalently to biologically active macromolecules such as antibodies. Metal complexes have also been used extensively in therapy. For radiotherapy, .alpha. and .beta. emitters of relatively short half-lives such as .sup.67 Cu, .sup.90 Y, .sup.212 Bi or .sup.225 Ac are strongly complexed by a ligand and are bound to an antibody. The chelates should not release their metal ions as the latter most often localize in the body and cause serious damage. For instance, free .sup.90 Y is known to concentrate in the bones where it causes myelosuppression and thus an increased risk of infection. Highly stable and kinetically inert metal chelates are thus desirable. In another medical application of metal chelates, .sup.157 Gd appears to be a promising agent for neutron capture therapy because of its very high thermal neutron capture cross section (J. L. Shih et al. Med. Phys. 19, 733-744, 1992) and again its use for curing tumors implies the formation of highly stable chelates.
The object of the present invention is a new approach to imaging and therapy with metal chelates that is illustrated schematically in FIGS. I.A-C.